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Genetic variation (CHRNA5), medication (combination nicotine replacement therapy vs. varenicline), and smoking cessation.

ABSTRACT: OBJECTIVE:Recent evidence suggests that the efficacy of smoking cessation pharmacotherapy can vary across patients based on their genotypes. This study tests whether the coding variant rs16969968 in the CHRNA5 nicotinic receptor gene predicts the effects of combination nicotine replacement therapy (cNRT) and varenicline on treatment outcomes. METHOD:In two randomized smoking cessation trials comparing cNRT vs. placebo, and varenicline vs. placebo, we used logistic regression to model associations between CHRNA5 rs16969968 and abstinence at end of treatment. RESULTS:For abstinence at end of treatment, there was an interaction between cNRT and rs16969968 (X(2)=8.15, df=2, omnibus-p=0.017 for the interaction); individuals with the high-risk AA genotype were more likely to benefit from cNRT. In contrast, varenicline increased abstinence, but its effect did not vary with CHRNA5. However, the genetic effects differed between the placebo control groups across two trials (wald=3.94, df=1, p=0.047), this non-replication can alter the interpretation of pharmacogenetic findings. CONCLUSIONS:Results from two complementary smoking cessation trials demonstrate inconsistent genetic results in the placebo arms. This evidence highlights the need to compare the most effective pharmacotherapies with the same placebo control to establish pharmacogenetic evidence to aid decisions on medication choice for patients trying to quit smoking.

SUBMITTER: Chen LS

PROVIDER: S-EPMC4537319 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Genetic variation (CHRNA5), medication (combination nicotine replacement therapy vs. varenicline), and smoking cessation.

Chen Li-Shiun LS Baker Timothy B TB Jorenby Douglas D Piper Megan M Saccone Nancy N Johnson Eric E Breslau Naomi N Hatsukami Dorothy D Carney Robert M RM Bierut Laura J LJ

Drug and alcohol dependence 20150623

<h4>Objective</h4>Recent evidence suggests that the efficacy of smoking cessation pharmacotherapy can vary across patients based on their genotypes. This study tests whether the coding variant rs16969968 in the CHRNA5 nicotinic receptor gene predicts the effects of combination nicotine replacement therapy (cNRT) and varenicline on treatment outcomes.<h4>Method</h4>In two randomized smoking cessation trials comparing cNRT vs. placebo, and varenicline vs. placebo, we used logistic regression to mo ...[more]

PMID: 26142345

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Project description:ImportanceSmoking cessation medications are routinely used in health care; it is vital to identify medications that most effectively treat this leading cause of preventable mortality.ObjectiveTo compare the efficacies of varenicline, combination nicotine replacement therapy (C-NRT), and the nicotine patch for 26-week quit rates.Design, setting, and participantsThree-group randomized intention-to-treat clinical trial occurring from May 2012 to November 2015 among smokers recruited in the Madison, Wisconsin, and Milwaukee, Wisconsin, communities; 65.5% of smokers offered the study (2687/4102) refused participation prior to randomization.InterventionsParticipants were randomized to one of three 12-week open-label smoking cessation pharmacotherapy groups: (1) nicotine patch only (n = 241); (2) varenicline only (including 1 prequit week; n = 424); and (3) C-NRT (nicotine patch + nicotine lozenge; n = 421). Six counseling sessions were offered.Main outcomes and measuresThe primary outcome was carbon monoxide-confirmed self-reported 7-day point-prevalence abstinence at 26 weeks. Secondary outcomes were carbon monoxide-confirmed self-reported initial abstinence, prolonged abstinence at 26 weeks, and point-prevalence abstinence at weeks 4, 12, and 52.ResultsAmong 1086 smokers randomized (52% women; 67% white; mean age, 48 years; mean of 17 cigarettes smoked per day), 917 (84%) provided 12-month follow-up data. Treatments did not differ on any abstinence outcome measure at 26 or 52 weeks, including point-prevalence abstinence at 26 weeks (nicotine patch, 22.8% [55/241]; varenicline, 23.6% [100/424]; and C-NRT, 26.8% [113/421]) or at 52 weeks (nicotine patch, 20.8% [50/241]; varenicline, 19.1% [81/424]; and C-NRT, 20.2% [85/421]). At 26 weeks, the risk differences for abstinence were, for patch vs varenicline, -0.76% (95% CI, -7.4% to 5.9%); for patch vs C-NRT, -4.0% (95% CI, -10.8% to 2.8%); and for varenicline vs C-NRT, -3.3% (95% CI, -9.1% to 2.6%). All medications were well tolerated, but varenicline produced more frequent adverse events than did the nicotine patch for vivid dreams, insomnia, nausea, constipation, sleepiness, and indigestion.Conclusions and relevanceAmong adults motivated to quit smoking, 12 weeks of open-label treatment with nicotine patch, varenicline, or C-NRT produced no significant differences in biochemically confirmed rates of smoking abstinence at 26 weeks. The results raise questions about the relative effectiveness of intense smoking pharmacotherapies.Trial registrationclinicaltrials.gov Identifier: NCT01553084.

Project description:Extended use of combined pharmacotherapies to treat tobacco dependence may increase smoking abstinence; few studies have examined their effectiveness. The objective of this study was to evaluate smoking abstinence with standard nicotine patch (NRT), extended use of combined formulations of nicotine replacement therapy (NRT+), or varenicline (VR).A total of 737 smokers, including those with medical and psychiatric comorbidities, were randomly assigned to one of the above three treatment conditions. The NRT group received 10 weeks of patches (21 mg daily maximum); the NRT+ group received patches (35 mg daily maximum) and gum or inhaler for up to 22 weeks; and the VR group received 1 mg twice daily for up to 24 weeks (22 weeks post target quit date). All participants also received six standardized 15-minute smoking cessation counseling sessions by nurses experienced in tobacco dependence treatment. The primary outcome was carbon monoxide-confirmed continuous abstinence rates (CAR) from weeks 5-52. Secondary outcomes were: CAR from weeks 5-10 and 5-22, and carbon monoxide-confirmed 7-day point prevalence (7PP) at weeks 10, 22, and 52. Adjusted and unadjusted logistic regression analyses were conducted using intention-to-treat procedures.The CARs for weeks 5-52 were 10.0 %, 12.4 %, and 15.3 % in the NRT, NRT+, and VR groups, respectively; no group differences were observed. Results with 7PP showed that VR was superior to NRT at week 52 (odds ratio (OR), 1.84; 97.5 % Confidence Interval (CI), 1.04-3.26) in the adjusted intention-to-treat analysis. Those in the VR group had higher CAR at weeks 5-22 (OR, 2.01; CI, 1.20-3.36) than those in the NRT group. Results with 7PP revealed that both NRT+ (OR, 1.72; CI, 1.04-2.85) and VR (OR, 1.96; CI, 1.20-3.23) were more effective than NRT at 22 weeks. As compared to NRT monotherapy, NRT+ and VR produced significant increases in CAR for weeks 5-10 (OR, 1.52; CI, 1.00-2.30 and OR, 1.58; CI, 1.04-2.39, respectively); results were similar, but somewhat stronger, when 7PP was used at 10 weeks (OR, 1.57; CI, 1.03-2.41 and OR, 1.79; CI, 1.17-2.73, respectively). All medications were well tolerated, but participants in the VR group experienced more fatigue, digestive symptoms (e.g., nausea, diarrhea), and sleep-related concerns (e.g., abnormal dreams, insomnia), but less dermatologic symptoms than those in the NRT or NRT+ groups. The frequency of serious adverse events did not differ between groups.Flexible and combination NRT and varenicline enhance success in the early phases of quitting. Varenicline improves abstinence in the medium term; however, there is no clear evidence that either varenicline or flexible, dual-form NRT increase quit rates in the long-term when compared to NRT monotherapy.ClinicalTrials.gov Identifier: NCT01623505 ; Retrospectively registered on July 13, 2011.

Project description:Background and aimsThe phase-based model of smoking cessation treatment suggests that treatment needs may vary across phases (e.g. pre-cessation, cessation). This study tested the comparative effects of varenicline and combination nicotine replacement therapy (C-NRT) relative to nicotine patch monotherapy on pre-cessation and cessation phase candidate withdrawal, expectancy and motivation mediators; relations between mediators and abstinence; and indirect effects of enhanced treatments on abstinence via candidate mediators.DesignSecondary mediation analysis of data from the open-label, randomized Wisconsin Smokers' Health Study 2, a comparative effectiveness trial of varenicline or C-NRT, versus patch monotherapy, in adults who smoked, recruited via media and community outreach.SettingResearch clinics in Madison and Milwaukee, Wisconsin, USA.ParticipantsA total of 1051 daily smokers motivated to quit smoking (52.5% female; mean age = 48.1, standard deviation = 11.6).InterventionsTwelve weeks of varenicline (n = 407) or 12 weeks of combination nicotine patch and nicotine lozenge therapy (n = 421), both compared with 12 weeks of patch control condition (n = 230), with individual smoking cessation counseling.MeasurementsThe primary abstinence outcome was biochemically verified 7-day point-prevalence abstinence 4 weeks post-target quit day (TQD). Candidate mediators (craving, positive smoking expectancies, withdrawal symptoms, and quitting motivation) were assessed via ecological momentary assessment from 1 week prior (pre-cessation phase) to 4 weeks after (cessation phase) the TQD.FindingsPre-cessation and cessation mean levels and slopes of craving [adjusted odds ratio (aOR) = 0.34-0.79], smoking expectancies (aOR = 0.46-0.79) and quitting motivation (aOR = 1.35-7.21) significantly predicted 4-week post-TQD abstinence (P < 0.05). Significant varenicline mediation occurred via greater suppression in pre-cessation craving [mediated effect (ab) = 0.09, standard error (SE) = 0.03, 95% confidence interval (CI) = 0.04-0.14] and smoking expectancies (ab = 0.06, SE = 0.02, 95% CI = 0.02-0.12). C-NRT mediation occurred via greater reduction in pre-post-TQD changes in craving (ab = 0.04, SE = 0.02, 95% CI = 0.01-0.08) and expectancies (ab = 0.03, SE = 0.02, 95% CI = 0.001-0.07), relative to patch monotherapy.ConclusionAmong adult smokers seeking to quit, varenicline seems to work through its effects on suppression of craving and smoking expectancies pre-cessation while combination nicotine replacement therapy mediation seems to work through cessation-related reduction in craving and smoking expectancies changes.

Project description:Background:Smoking cessation pharmacotherapies (SCPs) have been established as cost-effective for the treatment of tobacco use disorder across a variety of settings. In Jordan, a resource-constrained country where smoking rates rank at one of the highest globally, the cost-effectiveness of SCPs has not yet been quantified. The lack of information about the value of SCPs has contributed to low demand for them (from public and private payers) and consequently low availability of these medications. The aim of this study was to simulate-in a hypothetical cohort of Jordanian smokers-the clinical and economic impact of using two smoking cessation regimens and to generate cost-effectiveness values that can support policy changes to avail smoking cessation medication in a country burdened with heavy tobacco use. Methods:We employed a similar approach to a widely used economic model, the Benefits of Smoking Cessation on Outcomes (BENESCO) model. A hypothetical cohort of Jordanian male smokers aged 30 to 70?years and making a quit attempt using either a varenicline regimen or a nicotine replacement therapy (NRT) regimen were followed over time (until reaching 70?years of age). Markov simulations were run for the cohort, and life years gained were computed for each arm (compared to no intervention). Drug costs, prevalence of smoking, and population life expectancies were based on Jordanian data. Efficacy data were obtained from the literature. Incremental cost-effectiveness ratios as well as the potential budgetary impact of employing these regimens were generated. Several parameters were modified in sensitivity analyses to capture potential challenges unique to Jordan and that could impact the results. Results:For a treatment cohort of 527,118 Jordanian male smokers who intended to quit, 103,970 life years were gained using the varenicline regimen, while 64,030 life years were gained using the NRT regimen (compared to the no-intervention arm of life years). The cost per life year gained was JD1204 ($1696 USD) and JD1342 ($1890 USD) for varenicline and NRT, respectively.

Project description:Some smokers may benefit from a therapy that combines different nicotine replacement therapies (NRT) or drugs with different mechanisms of action.The aim of this study was to determine the efficacy of the combined therapy of varenicline and nicotine patches versus varenicline monotherapy.Three hundred forty-one smokers who smoked 20 or more cigarettes per day were recruited from a smoking cessation clinic between February 2012 and June 2013. The participants were randomized to receive a varenicline plus nicotine patch of 21 mg every 24 hours (170) or varenicline plus a placebo patch (171). All of the smokers received a standard 12-week course of varenicline and an 11-week course of either the placebo patch or the active patch after the target quit day. Both groups received behavioral support. The primary outcome was continuous abstinence for weeks 2 through 12 confirmed by exhaled levels of carbon monoxide. Post hoc subgroup analyses were performed to evaluate the treatment effects for a specific endpoint in subgroups of smokers.The combination of the nicotine patch with varenicline was not associated with higher rates of continuous abstinence at 12 weeks (39.1% versus 31.8%; odds ratio (OR) 1.24; 95% confidence interval (CI) 0.8 to 2.6) and 24 weeks (32.8% versus 28.2%; OR 1.17; 95% CI 0.4 to 1.9). When participants were analyzed by subgroups according to cigarette consumption, the abstinence rates among smokers who smoked more than 29 cigarettes per day at 12 weeks (OR 1.39; 95% CI 1.2 to 2.5) and 24 weeks (OR 1.46; 95% CI 1.2 to 2.8) were significantly higher in the combination group. Other post hoc analyses based on level of dependence and previous quit attempts did not show subgroup differences. No differences between the groups for the reported adverse events were observed (?2 value 0.07; P 0.79).The combination of varenicline with the nicotine patch does not improve abstinence rates at 12 and 24 weeks compared with varenicline used as monotherapy when all smokers were analyzed as a whole, independent of consumption level.This study is registered at clinicaltrial.gov (NCT01538394).

Project description:Introduction:The effectiveness of varenicline compared with nicotine replacement therapy (NRT) in achieving smoking cessation in older smokers has not been investigated. This study prospectively compared the effectiveness of varenicline relative to NRT in smokers aged 25-54 years and separately in smokers aged 55 years or older. Methods:Among 13 397 smokers participating in the Smoking Cessation Program in Taiwan, 2012-2015, 6336 (19.2%, aged ?55) received varenicline and 7061 received NRT patch or gum (23.2%, aged ?55). Participants self-reported smoking behaviors by phone interview after 6 months. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for 7-day, 1-month, and 6-month point-prevalence abstinence. Age-specific models adjusted for sex, education, marital status, smoke-years, nicotine dependence, medical institution, clinic visit number, and duration of medication received. Results:Among smokers aged 25-54 years, varenicline users had a greater point-prevalence abstinence than NRT users (e.g., 7-day point-prevalence: 34.0% vs. 23.5%), with adjusted OR ranging from 1.23 (CI: 1.09-1.39; 6-month point-prevalence) to 1.37 (CI: 1.24-1.50; 1-month point-prevalence). Among smokers aged 55 years or older, point-prevalence was similar for varenicline and NRT users (e.g., 7-day point-prevalence: 32.3% vs. 33.1%), and ORs did not suggest that varenicline has greater effectiveness than NRT. Sex and level of nicotine dependence did not modify the age-specific effectiveness of varenicline relative to NRT. Conclusions:Varenicline did not offer greater effectiveness in achieving abstinence than NRT for smokers 55 years or older, whereas it was more effective than NRT in smokers aged 25-54 years. These findings highlighted the need for age-specific approaches for effective tobacco control. Implications:In this prospective investigation of a national cohort, older smokers (aged ?55 years) who received varenicline did not have a greater point-prevalence abstinence after 6 months compared with those who used NRT patch or gum. Younger smokers (aged 25-54 years) who received varenicline had a greater likelihood of abstinence than NRT users. Sex and nicotine dependence did not modify the age-specific effectiveness of varenicline relative to NRT patch or gum. Age-appropriate approaches for effective tobacco control are needed.

Dataset Information

Genetic variation (CHRNA5), medication (combination nicotine replacement therapy vs. varenicline), and smoking cessation.

Publications

Genetic variation (CHRNA5), medication (combination nicotine replacement therapy vs. varenicline), and smoking cessation.

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